Molecular dynamics of the immune checkpoint Programmed Cell Death Protein I, PD-1: Conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

The immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy. PD-1 reduces the risk of autoimmunity by inducing apoptosis in antigen-specific T cells upon interaction with programmed cell death protein ligand I (PD-L1). Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. The clinically used blocking antibody nivolumab binds to PD-1 and inhibits the immunosuppressive interaction with PD-L1. Even though PD-1 is already used as a drug target the exact mechanism of the receptor is still unclear. For instance, the signal transduction from the extra- to the intracellular domain of PD-1 is still a matter of debate. It is hypothesized that the signal transduction is based on an active conformation of PD-1. Here we present the results of the first molecular dynamics simulations of PD-1 with a complete extracellular domain with a focus on the role of the BC-loop of PD-1 upon binding PD-L1 or nivolumab. We could identify that the BC-loop can form three conformations. Nivolumab binds to the BC-loop according to the conformational selection model whereas PD-L1 induces allosterically a conformational change of the BC-loop. Based on the structural differences of the BC-loop a signal transduction based on active conformation cannot be ruled out.